Within the last several years, exciting new avenues of potential immunotherapy of autoimmunity, have been described in animal models. Vaccination of rats with synthetic peptides corresponding to regions of T cell receptor beta chains have blocked subsequent development of EAE upon challenge with myelin basic protein. This model of T cell receptor peptide-based immunotherapy have recently been adapted to a mouse model in order to study and understand the mechanisms of this form of immunotherapy. A second form of potential immunotherapy has been based upon models of peptide-induced unresponsiveness. Projects outlined in this grant application intend to utilize these strategies of peptide- induced unresponsiveness in order to understand mechanisms of either T cell receptor peptide or immunodominant determinant peptide tolerance induction and to compare these models to the use of SEB to induce "anergy" and to apply these strategies to the treatment of EAE. Such studies have relevance to potential immunotherapeutic protocols in man. Groups of experimental animals will be treated with synthetic peptides corresponding either to regions of the T cell receptor V(beta)8.2 or to the immunodominant determinants of MBP or with SEB. Not only will such immunized or vaccinated mice be studied, but adoptive transfer and treatment of transgenic animals expressing the T cell receptor alpha/beta heterodimer corresponding to the receptor expressed on an encephalitogenic T cell clone will be studied. Anergy arising in T cells following peptide-induced unresponsiveness will be analyzed and compared to SEB-induced anergy in vivo and to a model system of anergy developed in vitro using a novel molecular methodology termed differential display to identify candidate "anergy genes." These studies may provide a cohesive foundation for the development of novel immunotherapeutic strategies for the treatment of multiple sclerosis.